(a) Field of the Invention
This invention relates to 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[(substituted phenylsulfinyl)alkanoyl]hydrazides and 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[(substituted phenylsulfonyl)alkanoyl]hydrazides that are useful as pharmacologic agents. These compounds are prostaglandin antagonists having analgesic activity. This invention also relates to 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[(substituted phenylthio]alkanoyl]hydrazides that are useful as intermediates in the preparation of the corresponding sulfinyl and sulfonyl compounds.
Analgesics are agents used in the treatment of pain and often are useful in alleviating inflammation. The major classes of analgesics include narcotic analgesics (or opiates) and analgesic-antipyretics such as the salicylates. Although the efficacy of opiates in relieving pain is well-established, the associated addiction liability is a distinct disadvantage. Although salicylate and salicylate-like agents (non-steroidal antiinflammatory agents) are also efficacious in relieving pain, they often exhibit undesirable side effects such as gastrointestinal irritation (as with aspirin), allergic response (as with aspirin), or liver toxicity with extended use (as with acetaminophen). The compounds included in this invention are neither opiates nor salicylates and may be expected not to exhibit the disadvantages of either class of compound.
(b) Prior Art
Related 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-(sulfinyl- and sulfonyl-containing acyl)hydrazides have been disclosed in a copending application, now U.S. Pat. No. 4,559,336, and related 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-(alkoxy-containing acyl)hydrazides have been disclosed in a copending application, now U.S. Pat. No. 4,559,337, both patents having the same assignee as the present application. Compounds in U.S. Pat. Nos. '336 and '337 are also prostaglandin antagonists having analgesic activity but differ from compounds of the present application in the composition of the acyl side chains.
The closest perior art discloses compounds of the following formula, wherein group B is carbonyl (CO) or sulfonyl (SO.sub.2) and A may be alkyl or substituted alkyl. The prior art does not, however, disclose nor anticipate the compounds of this invention. ##STR1##
More specifically, U.S. Pat. No. 3,534,019 discloses compounds in which B and A together constitute "lower alkanoyl," and U.S. Pat. No. 3,989,719 discloses compounds in which B and A together constitute "higher alkanoyl." Japanese Patent Application No. 128955/75 discloses compounds in which B is carbonyl and A is alkenyl, phenylalkenyl, and (cycloalkyl)alkyl. Thus, U.S. Pat. Nos. '019 and '719 and the Japanese application each disclose compounds in which A is a hydrocarbon. The thio-, sulfoxide-, and sulfone-containing compounds of this invention are not disclosed.
U.S. Pat. Nos. 4,045,442, 4,125,532 (division of '442), and 4,170,593 (division of '532) disclose compounds in which B is carbonyl and A is (substituted amino)alkyl. The sulfur-containing compounds of this invention are not disclosed.
U.S. Pat. Nos. 3,917,649 and 3,992,375 (division of '649) disclose compounds in which B is carbonyl or sulfonyl: where B is carbonyl, A may be haloalkyl, alkenyl, or aryloxyalkyl; and where B is sulfonyl, A may be alkyl, haloalkyl, aryl, or aralkyl. U.S. Pat. Nos. '649 and '375 thus disclose compounds in which a sulfonyl group must be attached directly to a hydrazine nitrogen, but do not disclose compounds in which B is carbonyl and A contains thio, sulfoxide, or sulfone groups. Thus, the compounds of this invention are structurally distinct from the prior art.